EP3782609B1 - Pelletformulierung mit einzelnem oder komplexem kräuterextrakt in hoher konzentration und herstellungsverfahren dafür - Google Patents
Pelletformulierung mit einzelnem oder komplexem kräuterextrakt in hoher konzentration und herstellungsverfahren dafür Download PDFInfo
- Publication number
- EP3782609B1 EP3782609B1 EP20176250.7A EP20176250A EP3782609B1 EP 3782609 B1 EP3782609 B1 EP 3782609B1 EP 20176250 A EP20176250 A EP 20176250A EP 3782609 B1 EP3782609 B1 EP 3782609B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- extract
- content
- seeds
- concentrate
- complex herbal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Definitions
- the present disclosure relates to a method for manufacturing a pellet formulation containing a single or complex herbal extract.
- Herbal medicines are drugs that are mainly prepared from plant medicinal herbs according to the principles of oriental medicine and prescription drugs that are formulated by combining plant medicinal herbs to be suitable for the treatment of disease symptoms.
- Herbal medicines are largely classified according to the formulating manner into: decoctions by a medicinal-herbs-in-package type of prescription, which is most general; single herbal extracts obtained by extracting, concentrating, and drying one kind of medicinal herb and then adding a plurality of excipients thereto, followed by granulation or powdering, for convenient dosing and long-term storage through change of a formulation; mixed herbal extracts made of single herbal extracts corresponding to constituent medicinal herbs of a prescription; and a complex herbal extract obtained by mixing, extracting, concentrating, and drying together constituent medicinal herbs of a prescription and adding a plurality of excipients thereto, followed by granulation or powdering.
- the complex herbal extracts may be differentiated by gamibang in which important constitutional medicinal herbs are added or removed.
- a patient can receive prescribed drugs in a pharmacy immediately after receiving a prescription from a doctor.
- a patient usually receives drugs 3-5 days after the treatment since a prescription established after the treatment is usually passed through a common decocting room, and the drugs have low convenience in carrying and dosing.
- Spray drying which is a physical method for making extract solid powders, is a drying method in which a liquid sample is dried over high-temperature hot air while being sprayed as atomized liquid droplets with a size of several tens to several hundreds of micrometers (10-200 ⁇ m), and thus made into a powder product, wherein the time of drying is approximately 5-30 s.
- Spray drying accounts for 80% or more of powdering methods.
- the spray-dried powder has problems of causing a lot of dust, being poor in flowability, being prone to moisture absorption or oxidation, and sticking together to forming a mass, during a subsequent treatment process or in handling by a user.
- plant extract solid powders have very high hygroscopicity due to a high content of carbohydrates containing sugar components.
- the extract powders dried by hot-air spray drying are produced by necessarily adding a drying aid agents in the range of 30-60% due to the characteristics of plant extracts. Additionally, 10-40% of excipients are further added in the manufacture of microgranules, granules, and pellets using the extract powders as base materials, resulting in a long processing time, low content of marker components, and especially many difficulties in handling raw materials due to hygroscopicity in the summer season.
- Glycyrrhizae Radix, Notopterygii Rhizoma, Lonicerae Flos, Platycodi Radix, Jujubae Fructus, Thujae Resina, Rehmanniae Radix, Anemarrhenae Rhizoma, Fraxini Cortex, and the like are medicinal herbs that are difficult to formulate with extracted solid powders due to high sugar contents thereof.
- drying aid agents carbohydrates with a high molecular weight, i.e., various starches, modified starches, dextrins, solid corn syrups, gum arabic, cyclodextrin, and the like, in the range of 30-70% relative to the dried solid content to increase glass transition temperatures. While DE 36 maltodextrin can be used as a drying aid agent to increase the drying temperature to 100°C, DE 5 maltodextrin can be used to increase the drying temperature to 188°C, thereby improving production efficiency.
- the prior art has suggested a method of extremely restricting the amount of an excipient, but such a method cannot increase the drying temperature relevant to the glass transition temperature in spray drying, resulting in extremely poor production efficiency, and thus is impossible to utilize industrially.
- the produced extract dry powders may necessarily have an excipient content in the range of 30-60%.
- Zizyphus jujuba, Rhemannia glutinosa, Panax ginseng, or a red ginseng concentrate powder having a high sugar content easily deteriorates in quality stability at room temperature due to hygroscopicity thereof, and has very low powder flowability due to high hygroscopicity, so that it is very difficult to conduct tableting and capsule filling in the productization procedure.
- the products manufactured by adding other excipients in large quantities in order to overcome these have a disadvantage of low content of active ingredients.
- pellets manufactured by extrusion and spheronization which are favorably applied to the manufacturing method for spherical pellets in western medicines
- dampening mass characteristics i.e., compressed plastic mass formability
- the pellets manufactured of microcrystalline cellulose and lactose have a hardness in the range of 0.48-0.73 kgf.
- the lactose acts as a binder when absorbing moisture, and therefore, the reduction of the lactose content results in a decrease in hardness of the pellets.
- the friability decreases as the density of the pellets increases, and the friability decreases as the compressive pressure increases. It is known that a friability of 0.71% or less is appropriate.
- the friability decreases as the compressive pressure increases.
- the screw pressure in extrusion is higher than those in the other methods, and thus the pellets manufactured by extrusion tend to show increased hardness and density, decreased friability, and somewhat delayed dissolution rates.
- sugar spheres with a diameter of 0.5-0.6 mm had a hardness of 0.09 kgf ⁇ 0.04 and a friability of 3.72% ⁇ 0.06, showing a very high level of friability. The appropriate level of friability was 1.7% or less in this report.
- the friability rate is determined by measuring the weight of the powder separated after rotation at a rate of 100-200 rpm for 5-10 min in a friability rate tester.
- the spray pressure of a preparation solution is in the range of 2.0-4.0 kg/cm 2 in an actual fluidized bed process, and thus seeds are placed under very highly severe conditions. As a result, small broken particles of the seeds stick to external portions of final products, or pellets are broken in half during the fluidized bed process, causing fatal damage to appearance quality of finished products.
- the rod-like granules and the like manufactured by a high shear mixing and granulator or vertical granulator have weak hardness, and thus seeds are broken in the subsequent fluidized bed coating process, and granules with small broken particles sticking thereto result in a lack of uniformity of the entire appearance and marketability.
- the conventional pellet formulation manufacturing methods did not consider physical characteristics, such as the content of sugar contained in an extract and viscosity of the extract, and thus, the viscosity continuously increases and heat is generated during the manufacture of pellets by common stirring and extrusion. As a result, a kneaded product that has not been extruded is hardened to cause instant mechanical resistance, and thus a screw may be stopped and screen holes may be clogged, and at last, a granulator may become inoperable.
- the present inventors made an effort to develop a method for manufacturing a pellet formulation containing a single or complex herbal extract at a high concentration. As a result, the present inventors developed: a method for manufacturing a pellet formulation, which contains a single or complex herbal extract at a high concentration and allows the identification of the contents of extract solids and marker components, by segmenting and classifying characteristics of original material extracts on the basis of the sugar content and optimizing a variety of associated factors; and a method for manufacturing a pellet formulation containing a capsule having an essential oil encapsulated therein, and as a result, completed the present disclosure.
- an aspect of the present disclosure is to provide a method for manufacturing a pellet formulation containing a single or complex herbal extract.
- the invention is set out in the appended set of claims.
- a method for manufacturing a pellet formulation containing a single or complex herbal extract comprising:
- the present inventors made an effort to develop a method for manufacturing a pellet formulation containing a single or complex herbal extract at a high concentration. As a result, the present inventors developed a method for manufacturing a pellet formulation, which contains a single or complex herbal extract at a high concentration and allows the identification of the contents of extract solids and marker components, by segmenting and classifying characteristics of original material extracts on the basis of the sugar content and optimizing a variety of associated factors.
- a method for manufacturing a pellet formulation of the present disclosure is largely composed of a step for preparing a concentrate for seeds and a concentrate for fluidized bed coating, molding seeds and coating surfaces of the seeds.
- the term seed refers to a small particle that is a core of a pellet in the manufacture of a pellet formulation of the present disclosure. While the seed is coated with an extract, an excipient, and the like, the particle is grown to a desired size, so that a pellet is manufactured.
- a single or complex herbal extract is concentrated into a concentrate for seeds and a concentrate for fluidized bed coating under different concentration conditions, respectively.
- single herbal medicine refers to one kind of medicinal herb, including (i) plant herbs and (ii) roots, barks, flowers, fruits, seeds, or rhinoceros horns, which are natural products that are used per se as a drug product or used as a raw material for medicines.
- the single herbal medicine in the present disclosure includes Puerariae Radix, Chrysanthemi Flos, Glycyrrhizae Radix, Notopterygii Rhizoma, Zingiberis Rhizoma Siccus, Cinnamomi Ramulus, Agastachis Herba, Trichosanthis Semen, Lonicerae Flos, Platycodi Radix, Angelicae Gigantis Radix, Jujubae Fructus, Rhei Rhizoma, Persicae Semen, Angelicae Pubescentis Radix, Ephedrae Herba, Viticis Fructus, Liriopes Radix, Hordei Fructus Germiniatus, Moutan Cortex, Aucklandiae Radix, Menthae Herba, Pinelliae Rhizoma, Saposhnikovia Radix, Thujae Resina, Atractylodis Rhizoma Alba, Poria (Hoelen), Am
- complex herbal medicine is composed of one or more kinds of medicinal herbs, and the complex herbal medicine contains individual medicinal compositions by an herbal medicine manufacturing instruction or a prescription.
- the complex herbal medicine may include a combination of single herbal medicines and individual medicinal compositions in any appropriate manner, such as a combination of one or more kinds of single herbal medicines and a combination of one or more kinds of single herbal medicines and an individual medicinal composition by one or more prescriptions.
- the individual medicinal composition in a prescription includes Gamisoyosan, Galgeun-tang, Galgeunhaegi-tang, Gumigangh wal-tang, Dangguiyukhwang-tang, Dashiho-tang, Daecheongryong-tang, Daehwajungeum, Daehwangmokdanpi-tang, Doinseunggi-tang, Mahwang-tang, Banhabaekchulcheonma-tang, Banhasasim-tang, Banhahubak-tang, Baekchul-tang, Bojungikgi-tang, Bohe-tang, Bokryeongbosim-tang, Bulhwangeumjeonggisan, Samsoum, Samchulgeonbi-tang, Saengmaeksan, Sosiho-tang, Yeongyangjihwang-tang, Palmul-tang, and Pyeongwisan, but is not limited thereto.
- step (a) may further include an extraction step for obtaining the single or complex herbal extract.
- the extraction may employ various extraction methods commonly known in the art.
- extract refers to a solvent crude extract, a particular solvent-soluble extract (solvent fraction), and a solvent fraction of a solvent crude extract, for the single or complex herbal medicine.
- the extract may be a crude extract obtained by subjecting a single herbal medicine and/or a complex herbal medicine to extraction with at least one solvent selected from the group consisting of water and a straight-chain or branched alcohol having 1 to 4 carbon atoms, and for example, the extract may be a crude extract obtained by extraction with water as a solvent.
- an aqueous solution of a straight-chain or branched alcohol having 1 to 4 carbon atoms may be used in 10 or more and less than 100 %(v/v), 20 or more and less than 100 %(v/v), 30 or more and less than 100 %(v/v), 40 or more and less than 100 % (v/v), 50 or more and less than 100 %(v/v), 60 or more and less than 100 %(v/v), or 70 or more and less than 100 % (v/v) .
- the aqueous solution of an alcohol may be one kind selected from the group consisting of an aqueous solution of methanol, an aqueous solution of ethanol, an aqueous solution of propanol, and an aqueous solution of butanol.
- the extract according to the present disclosure may be a solvent fraction obtained by fractionating the solvent crude extract with an additional solvent, and for example, may be a solvent fraction of the solvent crude extract, obtained by using at least one kind of solvent selected from the group consisting of ethyl ether, ethyl acetate, and butanol.
- the extract may be a solvent fraction obtained by fractionating a solvent crude extract with at least one kind of solvent selected from the group consisting of ethyl ether, ethyl acetate, and butanol, the solvent crude extract being obtained by subjecting the single herbal medicine and/or complex herbal medicine to extraction with at least one solvent selected from the group consisting of water and a straight-chain or branched alcohol having 1 to 4 carbon atoms.
- the extract may be obtained by adding water as a solvent to a single herbal medicine and/or complex herbal medicine and immersing the medicine in the water.
- extract solid refers to a solid material contained in the extract, and the extract solid may be obtained by drying, for example, spray-drying the extract, but is not limited thereto.
- the method may further include, before step (a), a step of measuring the sugar content of the single herbal medicine or complex herbal medicine.
- a single herbal medicine or complex herbal medicine is sorted according to the sugar content of a 10-fold water extract of the single herbal medicine or complex herbal medicine, and then a concentrate for seeds and a concentrate for fluidized bed coating having a lower sugar content than the concentrate for seeds are prepared.
- the concentrate for seeds in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 45-65 Brix.
- the concentrate for fluidized bed coating in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 15-35 Brix.
- the single herbal medicine of which a 10-fold water extract has a sugar content of 5.5 or more and less than 10.0 Brix
- the complex herbal medicine, of which a 10-fold water extract has a sugar content of 5.5 or more and less than 10.0 Brix may include Gumiganghwal-tang and Yeongyangjihwang-tang, but are not limited thereto.
- the concentrate for seeds in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 40-60 Brix.
- the concentrate for fluidized bed coating in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 25-45 Brix.
- the single herbal medicine of which a 10-fold water extract has a sugar content of 3.0 or more and less than 5.5 Brix
- the complex herbal medicine, of which a 10-fold water extract has a sugar content of 3.0 or more and less than 5.5 Brix may include Galgeun-tang, Dangguiyukhwang-tang, Daehwajungeum, Mahwang-tang, Banhasasim
- the concentrate for seeds in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 30-60 Brix.
- the concentrate for fluidized bed coating in step (a) may be prepared by concentrating the single or complex herbal extract to a sugar content of 20-35 Brix.
- the single herbal medicine of which a 10-fold water extract has a sugar content of 0.01 or more and less than 3.0 Brix
- the method for manufacturing a pellet formulation of the present disclosure may further include: a step of obtaining an essential oil volatilized during extraction and concentration; and a step of encapsulating the essential oil.
- the essential oil may be obtained by subjecting the single or complex herbal medicine to extraction and concentration in an extractor and concentrator equipped with essential oil encapsulating, condensing, and separating devices, and the obtained essential oil component may be encapsulated using alginic acid or beta-cyclodextrin, and added to the concentrate for fluidized bed coating in step (c).
- the aromatic single herbal medicine may include Nardostachyos Rhizoma, Dalbergiae Odoriferae Lignum, Osterici Radix, Agastachis Herba, Cinnamomi Ramulus, Aucklandiae Radix, Saposhnikovia Radix, Alpiniae Japonicae Semen, Menthae Herba, Santali Albi Lignum, Moschi Moschus, Thymi Herba, Styrax Liquides, Lysimachiae Foeni-graeci Herba, Olibanum, Cinnamomi Cortex Spissus, Myristicae Semen powder, Pterocarpi Lignum, Syzygii Flos, Atractylodis Rhizoma, Aquilariae Resinatum Lignum, Helenii Radix, Pini Semen, and Sesami Oleum, but is not limited thereto.
- the excipient is at least one kind selected from the group consisting of precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide (MgO), calcium silicate (CaSiO 3 ), magnesium silicate (3MgSiO 3 ⁇ 5H 2 O), silicon dioxide (SiO 2 ), titanium dioxide (TiO 2 ), bentonite, kaolin, talc, CMC-Ca, casein, dextrin, hydroxypropyl methylcellulose (HPMC), pullulan, microcrystalline cellulose (MCC), lactose, stearic acid-magnesium (stearate-Mg), stearic acid-calcium (stearate-Ca), PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate (SSOC), and sucrose fatty acid ester.
- CaCO 3 precipitated calcium carbonate
- MgO magnesium oxide
- CaSiO 3 calcium silicate
- a concentrate for seeds which contains 35-55 wt% of single or complex herbal extract solids relative to the total dry weight of the seeds, may be mixed with the balance of an excipient.
- the excipient may contain, relative to the total weight of excipients: 74-83 wt% of at least one kind of release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate; 15-25 wt% of at least one kind of mineral additive selected from the group consisting of precipitated calcium carbonate, magnesium oxide, calcium silicate, magnesium silicate, silicon dioxide, titanium dioxide, bentonite, kaolin, and talc; and 1-2 wt% of sucrose fatty acid ester as an emulsifier.
- release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate
- a concentrate for seeds which contains 45-65 wt% of single or complex herbal extract solids relative to the total dry weight of the seeds, may be mixed with the balance of an excipient.
- the excipient may contain, relative to the total weight of excipients: 78-88 wt% of at least one kind of release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate; 10-20 wt% of at least one kind of mineral additive selected from the group consisting of precipitated calcium carbonate, magnesium oxide, calcium silicate, magnesium silicate, silicon dioxide, titanium dioxide, bentonite, kaolin, and talc; and 1-2 wt% of sucrose fatty acid ester as an emulsifier.
- release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate
- a concentrate for seeds which contains 50-70 wt% of single or complex herbal extract solids relative to the total dry weight of the seeds, may be mixed with the balance of an excipient.
- the excipient may contain, relative to the total weight of excipients: 83-94 wt% of at least one kind of release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate; 5-15 wt% of at least one kind of mineral additive selected from the group consisting of precipitated calcium carbonate, magnesium oxide, calcium silicate, magnesium silicate, silicon dioxide, titanium dioxide, bentonite, kaolin, and talc; and 1-2 wt% of sucrose fatty acid ester as an emulsifier.
- release agent selected from the group consisting of microcrystalline cellulose, lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, starch sodium octenyl succinate
- the step of mixing the concentrate for seeds and the excipient to mold seeds may include: a step of passing a mixture of the concentrate for seeds and the excipient through an extruder to cut an extrudate; and introducing the cut extrudate into a spheronizer to grind the cut extrudate.
- a kneaded product obtained by mixing the extract with an excipient has increased stickiness due to sugar components. While the kneaded product is re-mixed and compressed by the rotation of a screw inside a cylinder of an extruder, the kneaded product has rapidly increased viscosity and generates heat due to friction inside the cylinder, causing the hardening of the contents, with the result screen holes may be clogged, or the kneaded product is lengthily extruded and thus are not easily cut.
- the mixture of the concentrate for seeds and the excipient is allowed to pass through an extruder equipped with an extrusion part disc having a hole length of 1.0-2.0 cm, 1.0-1.9 cm, 1.0-1.8 cm, 1.0-1.7 cm, 1.0-1.6 cm, 1.1-2.0 cm, 1.1-1.9 cm, 1.1-1.8 cm, 1.1-1.7 cm, 1.1-1.6 cm, 1.3-2.0 cm, 1.3-1.9 cm, 1.3-1.8 cm, 1.3-1.7 cm, 1.3-1.6 cm, 1.4-2.0 cm, 1.4-1.9 cm, 1.4-1.8 cm, 1.4-1.7 cm or 1.4-1.6 cm and a hole diameter of 1.0-2.0 mm, 1.0-1.9 mm, 1.0-1.8 mm, 1.0-1.7 mm, 1.0-1.6 mm, 1.1-2.0 mm, 1.1-1.9 mm, 1.1-1.8 mm, 1.1-1.7 mm, 1.1-1.6 mm, 1.3-2.0 mm, 1.3-1.9 mm,
- the cut extrudate is introduced into a spheronizer, followed by grinding, thereby manufacturing spherical pellets usable as basic seeds for the pellet formulation of the present disclosure.
- the seeds are used as cores for the pellet formulation of the present disclosure.
- the seeds produced in step (b) are introduced into a fluidized bed granulator to be fluidized, and a mixture of the concentrate for fluidized bed coating and an excipient is sprayed to grow the seeds into a pellet formulation.
- the seeds are introduced into the fluidized bed granulator, and then the mixture of the liquid-concentrate for fluidized bed coating and the excipient may be sprayed from the bottom portion of the fluidized bed granulator in a bottom-spray manner or from the top portion of the fluidized bed granulator in a top-spray manner.
- the mixture may be sprayed from the bottom portion of the fluidized bed granulator in a bottom-spray manner.
- the preparation solution to be sprayed is required to have appropriate viscosity and sticking strength, retain uniform spreadability on the particle surface, and prevent agglomeration by mitigating the sticking strength of sugar components.
- the sugar content of the concentrate used for fluidized bed coating is differently adjusted according to characteristics of medicinal herbs, and the kind of the excipient used and the additional amount thereof are adjusted, so that the concentrate is promptly dried and does not have excessive sticking strength by sugar components even though the liquid is concentrated.
- the excipient mixed with the concentrate for fluidized bed coating may be used in 10-15 wt% relative to single or complex herbal extract solids, which are contained in the concentrate for fluidized bed coating.
- the excipient may contain, relative to the total weight thereof: 40-50 wt% of at least one kind selected from the group consisting of precipitated calcium carbonate, stearic acid-magnesium, and PEG 6000; 5-15 wt% of at least one kind selected from the group consisting of HPMC, pullulan, and glutinous rice starch; 35-45 wt% of starch sodium octenyl succinate; and 2-8 wt% of sucrose fatty acid ester.
- the excipient mixed with the concentrate for fluidized bed coating may be used in 5-10 wt% relative to single or complex herbal extract solids, which are contained in the concentrate for fluidized bed coating.
- the excipient may contain, relative to the total weight thereof: 15-25 wt% of at least one kind selected from the group consisting of precipitated calcium carbonate, stearic acid-magnesium, and PEG 6000; 25-35 wt% of at least one kind selected from the group consisting of HPMC, pullulan, and glutinous rice starch; 35-45 wt% of starch sodium octenyl succinate; and 2-8 wt% of sucrose fatty acid ester.
- the excipient mixed with the concentrate for fluidized bed coating may be used in 3-8 wt% relative to single or complex herbal extract solids, which are contained in the concentrate for fluidized bed coating.
- the excipient may contain, relative to the total weight thereof: 5-15 wt% of at least one kind selected from the group consisting of precipitated calcium carbonate, stearic acid-magnesium, and PEG 6000; 50-70 wt% of at least one kind selected from the group consisting of HPMC, pullulan, and glutinous rice starch; 35-45 wt% of starch sodium octenyl succinate; and 2-8 wt% of sucrose fatty acid ester.
- the method may further include, after step (c), a step of coating a surface of the pellet formulation produced in step (c).
- various moisture-proof coating materials known in the art may be selected and used.
- the moisture-proof coating material includes starch, gelatin, natural edible dyes, artificial edible dyes, cellulose, biodegradable polymers, biodegradable oligomers, emulsifying wax, shellac, flavoring agents, hydrophobic agents or hydrophilic agents, lipids, proteins, and minerals.
- the moisture-proof coating material at least one kind selected from the group consisting of hydroxy propyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, methylcellulose, titanium dioxide, polyethylene glycol, triethyl citrate, triacetin, dibutyl sebacate, polymethacrylate, cellulose acetate phthalate, carnauba wax, candelilla wax, petroleum wax, beeswax, and hydrogenated fat may be used, and for example, shellac or ethyl cellulose may be used, but is not limited thereto.
- the moisture-proof coating material may be used in 1-5 wt%, 1-4 wt%, or 1-3 wt%, and for example 2 wt%, relative to the sum of the weight of the seeds introduced into the fluidized bed granulator and the dry weight of the mixture of the concentrate for fluidized bed coating and the excipient, which has been sprayed on the surfaces of the seeds, in step (c).
- the surface of the pellet formulation produced in step (c) of the present disclosure is coated with a moisture-proof material, thereby improving stability in storage and safety in the distribution procedure.
- an herbal medicinal prescription can be easily configured by combining pellet formulations manufactured by the method of the present disclosure, with the results that the content of the medicine contained in finally administered extract solids can be easily adjusted, and thus by raising or lowering the content of a particular marker component in the herbal medicinal prescription, a prescription can be easily adjusted in response to the degrees of personal disease symptoms and the personal constitution. Furthermore, in the event of side effects, the accurate understanding of causes thereof and the derivation of remedies are easily attained.
- the present disclosure provides a pellet formulation containing a single or complex herbal extract, the pellet formulation being manufactured by the method of the present disclosure.
- pellet formulation containing a single or complex herbal extract of the present disclosure is manufactured by the manufacturing method of the present disclosure, the descriptions of overlapping contents therebetween will be omitted to avoid excessive complication of the specification due to repetitive descriptions thereof.
- the pellet formulation manufactured by the method of the present disclosure may have a spherical or oval shape, and for example, a spherical shape.
- the pellet formulation containing a single or complex herbal extract, manufactured by the method of the present disclosure contains 55-95 wt% of extract solids in an extract, which is an active ingredient showing a pharmaceutical effect.
- a pellet formulation manufactured using a single or complex herbal extract contains 55-80 wt% of extract solids of a single or complex herbal medicine when a 10-fold water extract of the single or complex medicine has a sugar content of 5.5 or more and less than 10.0 Brix; a pellet formulation manufactured using a single or complex herbal extract contains 60-90 wt% of extract solids of a single or complex herbal medicine when a 10-fold water extract of the single or complex medicine has a sugar content of 3.0 or more and less than 5.5 Brix; and a pellet formulation manufactured using a single or complex herbal extract contains 70-95 wt% of extract solids of a single or complex herbal medicine when a 10-fold water extract of the single or complex medicine has a sugar content of 0.01 or more and less than 3.0 Brix.
- the pellet formulation of the present disclosure can be utilized for a pharmaceutical composition, a food composition, a health functional food, an herbal medicinal product, and various basic processed products.
- the pellet formulation of the present disclosure may be used as a non-prescription drug purchasable without a prescription, a botanical drug, an herbal medicine, a homeopathic agent supplier, or a supplement, and may be contained as a nutritional component in a food, a functional food, a beverage, bar, a food additive, a medicinal food, a dietary supplement, or an herb product.
- the present disclosure relates to a method for manufacturing a pellet formulation containing a single or complex herbal extract.
- the invention is set out in the appended set of claims.
- a method for manufacturing a pellet formulation which has a high content of extract solids and attain improved production efficiency, was completed by segmenting and classifying characteristics of original material extracts on the basis of the sugar content and optimizing a variety of associated factors in the manufacture of a pellet formulation through the preparation of seeds and a fluidized bed coating process for coating the prepared seeds.
- a pellet formulation When a pellet formulation is manufactured using the manufacturing method of the present disclosure, the contents of solids and marker components in herbal extracts can be monitored, and an herbal medicinal prescription can be easily configured by combining the manufactured pellet formulations. Furthermore, the content of the extract solids administered can be easily adjusted, and thus by raising or lowering the content of a particular marker component in the herbal medicinal prescription, a prescription can be easily adjusted in response to the degrees of personal disease symptoms and the personal constitution, and in the event of side effects, the accurate understanding of causes thereof and the derivation of remedies are easily attained.
- % used to express the concentration of a specific material, unless otherwise particularly stated, refers to (wt/wt)% for solid/solid, (wt/vol)% for solid/liquid, and (vol/vol)% for liquid/liquid.
- extract dry powders has a problem in that the contents of herbal extract solids or marker components contained in final products get gradually smaller since various kinds of excipients are added in the manufacture of powders in a spray drier, the preparation of seeds, and the preparation of a preparation solution for fluidized bed spraying
- the rod-like granules and the like manufactured by a high shear mixing and granulator or vertical granulator have weak hardness, and thus seeds are broken in the subsequent fluidized bed coating process, and granules with small broken particles sticking thereto result in a lack of uniformity of the entire appearance and marketability.
- the conventional pellet formulation manufacturing methods did not consider physical characteristics, such as the content of sugar contained in an extract and viscosity of the extract, and thus, the viscosity continuously increases and heat is generated during the manufacture of pellets by common stirring and extrusion. As a result, a kneaded product that has not been extruded is hardened to cause instant mechanical resistance, and thus a screw may be stopped and screen holes may be clogged, and at last, a granulator may become inoperable.
- a prescription of a complex herbal medicine using a combination of single herbal medicines, manufactured by the method of the present disclosure can be promptly delivered on the spot. Furthermore, in cases where the complex herbal medicine manufactured by the method of the present disclosure is required to effectively reduce disease symptoms of a patient, the weight of a single herbal medicine containing an important marker component corresponding to the requirement can be easily increased or decreased, and finally, a personal customized prescription of herbal medicines can be promptly made. Therefore, the herbal formulation of the present application can be effectively applied in an apparatus for automatic mixing and manufacturing herbal medicinal prescriptions.
- Example 1 Classification of single herbal extracts and complex herbal extracts according to sugar content of extract
- Each herbal medicine 200g was introduced into an extractor, and 10-fold purified water 2000 g was introduced thereinto, followed by extraction at 95°C for 2 hours.
- the sugar content of the extract was measured (Atago Digital saccharometer Pal-3), and the content of solids contained in the extract was measured by an infrared moisture analyzer (FD-720, KETT Electronic, Japan). The measurement was repeatedly conducted three times.
- the single herbal medicines were classified into 1 high-sugar-content single herbal medicines having a sugar content of 5.5 or more and less than 10.0 Brix in the extracts, 2 medium-sugar-content single herbal medicines having a sugar content of 3.0 or more and less than 5.5 Brix in the extracts, and 3 low-sugar-content single herbal medicines having a sugar content of 0.01 or more and less than 3.0 Brix in the extracts.
- the high-sugar-content single herbal medicines encompass 17 kinds of single herbal medicines ranging from the Atractylodis Rhizoma Alba extract having a sugar content of 5.8 to the Rehmanniae Radix Preparat extract having a sugar content of 9.0 and account for 25.8%; and the medium-sugar-content single herbal medicines encompass 15 kinds of single herbal medicines ranging from the Angelicae Pubescentis Radix having a sugar content of 3.2 and the Gastrodiae Rhizoma extract having a sugar content of 3.15 to the Schizandrae Fructus extract having a sugar content of 5.0 and account for 22.7%.
- the low-sugar-content single herbal medicines encompass 34 kinds of single herbal medicines largely ranging from the Poria(Hoelen) extract having a sugar content of 0.04 and the Magnoliae Cortex extract having a sugar content of 0.7 to the Puerariae Radix extract having a sugar content of 2.95 and account for 51.5%. Then, as shown in Table 2, five kinds for each of high-, medium-, and low-sugar-content single herbal medicines were randomly selected from the 66 kinds of single herbal medicines. Out of the selected herbal medicines, aromatic materials are Atractylodis Rhizoma and Cinnamomi Cortex Spissus.
- the 10-fold water extracts based on the weights of medicinal herbs of the complex herbal decoctions were measured to have similar sugar content ranges to medium- and low-sugar-content single herbal medicines. Therefore, based on the sugar content and solid content measurement results of the extracts of 26 kinds of complex herbal decoctions in Table 3, the complex herbal decoctions, like the single herbal medicines, were classified into 1 high-sugar-content complex herbal decoctions having a sugar content of 5.5 or more and less than 10.0 Brix in the extracts, 2 medium-sugar-content herbal decoctions having a sugar content of 3.0 or more and less than 5.5 Brix in the extracts, and 3 low-sugar-content herbal decoctions having a sugar content of 0.01 or more and less than 3.0 Brix in the extracts.
- the extracts of the complex herbal decoctions showed a tendency in which, as the content percentage of a raw material corresponding to the high-sugar-content signal herbal medicines increases, the sugar content of the extract also increases.
- 2 kinds (7.7%), 15 kinds (57.7%), and 9 kinds (34.6%) corresponded to the high-, medium-, and low-sugar-content extracts, respectively. Consequently, when multiple single herbal medicines were mixed, the mixture was changed into a medium-sugar-content extract, accounting for 57% or more. Therefore, 90% of the complex herbal decoctions corresponded to the extracts of the medium- or low-sugar-content complex herbal decoctions.
- Example 2 Preparation of seeds by extruder and spheronizer, and spherical pelletizing of seeds by fluidized bed granulator
- An extruder equipped with a dome-type screen and a spheronizer (Enger E-50 extruder and S-250 Spheronizer) were used for the manufacture of spherical pellets by the conventional method, and an extruder used in the present disclosure includes an extruder die mold part having a plurality of circular extrusion holes, instead of the screen, as shown in FIG. 3 .
- the extrusion holes, through which an extrudate passes, have a shape with a length of 1-2 cm and a diameter of 1-1.5 mm, and a cutting part with a plurality of rotary-type knife blades for cutting the extrudate into a length of 1-1.5 mm were disposed on the front surface of the die part.
- a kneaded product obtained by adding an herbal extract concentrate or an herbal extract dry powder and an excipient is transferred into a cylinder of an extruder, and while a screw is rotated, the kneaded product is remixed and compressed, and thus has rapidly increased viscosity and generates heat by friction inside the cylinder, causing the hardening of the contents, with the result that existing screen holes may be clogged, or the kneaded product is lengthily extruded and thus is not easily naturally cut, unlike extrudates of western medicines.
- a cylindrical extrudate is easily cut to a length of 2-4 times the diameter, and when the extrudate cut to a length of 2-4 times the diameter is introduced into the spheronizer, the extrudate is relatively easily ground due to weak stickiness and hardness thereof, with the result that a spherical pellet shape can be made within 5-10 minutes.
- a rectangular cylindrical extrudate formed of an herbal extract concentrate or an herbal extract dry powder has high hardness due to high stickiness thereof, and thus when a spheronizer is operated, the extrudate cannot be easily cut to a shorter length due to internal friction and collision, and even though the extrudate is artificially cut into a length of 2-4 times the diameter, like extrudates of western medicines, and introduced into the spheronizer, the extrudate is made into a rectangular cylindrical shape. Therefore, when again coated with an herbal extract concentrate in a fluidized bed apparatus, such a product is made into pellets with a very bulging appearance.
- the cut length of an extrudate was 1.5 mm, that is, samples obtained by cutting the extrudate to be equal in length and diameter were ground at 1500 rpm for 10 min corresponding to the same conditions as in 1 in a spheronizer, and the ground samples were sieved. Then, 1.0-1.4 mm-sized seeds were introduced into a fluidized bed granulator, and sprayed with an Ephedrae Herba concentrate, thereby manufacturing a final formulation.
- Table 5 shows the grinding results of the extrudate manufactured by the conventional method and the extrudate manufactured by the method of the present disclosure, and grinding was repeated seven times for 200 g of an extrudate for each time.
- 2.8 to 2.0 mm- and 1.4 to 1.0 mm-sized seeds were used as seeds for a fluidized bed apparatus, respectively.
- the production efficiency values of pellets with a size that can be used as seeds were 83.2% and 92.2%, respectively, and showed an increase tendency when the length was equal to the diameter in the extrudate.
- the reason why the deviation was large in the size of 2.0-2.8 mm for the dome type screen was that pellets standing at right angles passed through the sieve during sieving. All the finished seeds had a hardness of 17-19 kgf, which was considered to be significantly hard.
- Mahwang-tang belongs to the medium-sugar-content medicines according to the classification criteria of the present application, and the operating conditions of the fluidized bed granulator followed those presented in Table 6 below.
- FIGS. 4A and 4B show changes from seeds to finished spherical pellets during the above procedure and spherical pellets finished using seeds manufactured according to the extrusion hole diameters.
- FIG. 5 illustrates images showing the color coating of finished spherical pellets. The weight of TiO 2 used was 1% per weight of spherical pellets to be coated, and the pellets were white coated and then coated with a color extracted from red radish.
- an extract concentrate and an excipient were mixed and kneaded, and the kneaded product was passed through extruders including extruder die parts in which extrusion holes with diameters of 1, 1.2, and 1.5 mm were applied to discs having extrusion holes with lengths of 1, 1.5, and 2 cm.
- the square cylindrical extrudate thus obtained was introduced into a spheronizer, and ground at 1500 rpm for 10 min, thereby manufacturing spherical pellets usable as seeds.
- the extrudate hardness by screw compression was measured in the range of 17-19 kgf, and thus can be used as seeds for a fluidized bed granulator, without breakage or friability, thereby improving the appearance shape of final products.
- sucrose fatty acid ester as an emulsifier was used, a combination of stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, colloidal silicon dioxide, silicon dioxide powder, zein powder, starch sodium octenyl succinate, lactose, precipitated calcium carbonate, microcrystalline cellulose, kaolin, talc, CMC-Ca, casein, and dextrin (DE 10 or less) was used as a releasing agent and an anti-caking agent, and HPMC and pullulan were used as a binder.
- sucrose fatty acid ester as an emulsifier was used, a combination of stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, colloidal silicon dioxide, silicon dioxide powder, zein powder, starch sodium octenyl succinate, lactose, precipitated calcium carbonate, microcrystalline cellulose
- At least one kind of excipient including microcrystalline, beta-cyclodextrin powder, starch sodium octenyl succinate, and the like was used at a weight of 74-83 g
- at least one of excipients including precipitated calcium carbonate, silicon dioxide powder, stearic acid-magnesium, and the like was used at a weight of 15-25 g
- sucrose fatty acid ester as an emulsifier was used at a weight of 1-2 g, relative to 100 g of the total excipients.
- At least one kind of excipient including microcrystalline, beta-cyclodextrin powder, starch sodium octenyl succinate, and the like was used at a weight of 78-88 g
- at least one kind of excipient including precipitated calcium carbonate, silicon dioxide powder, stearic acid-magnesium, and the like was used at a weight of 10-20 g
- sucrose fatty acid ester as an emulsifier was used at a weight of 1-2 g, relative to 100 g of the total excipients.
- At least one kind of excipient including microcrystalline, beta-cyclodextrin powder, starch sodium octenyl succinate, and the like was used at a weight of 83-94 g
- at least one kind of excipient including precipitated calcium carbonate, silicon dioxide powder, stearic acid-magnesium, and the like was used at a weight of 5-15 g
- sucrose fatty acid ester as an emulsifier was used at a weight of 1-2 g, relative to 100 g of the total excipients.
- Jujubae Fructus, Fraxini Cortex, Ginseng Radix, Glycyrrhizae Radix, and Scutellariae Radix selected among the high-sugar-content single herbal medicines were subjected to massive extraction, and then the concentrates thereof were prepared.
- the concentrate of each extract was divided into concentrates for two-type purposes. That is, a concentrate for seed preparation and a concentrate for fluidized bed coating were separately prepared.
- Each kind of single herbal medicine was immersed in purified water for 30 min after the purified water was added at a weight of 250 kg per 25 kg of the single herbal medicine, and then subjected to extraction at 95-100°C for 3 h, and thereafter, the 10-fold water extract was transferred to a reduced pressure concentrator, and then concentrated under reduced pressure while the temperature was maintained at 60°C.
- the 10-fold water extract 1/3 of the extract and 2/3 of the extract were concentrated to have different sugar contents for seeds and for a fluidized bed, respectively.
- the sugar content was measured by Atago digital saccharometer (Pal-3) and the content of solids was measured by an infrared moisture analyzer (FD-720, KETT Electronic, Japan), and calculated. Table 8 shows the results of extraction and concentration.
- Atractylodis Rhizoma, Coptidis Rhizoma, Zingiberis Rhizoma Recens, Paeoniae Radix, and Ephedrae Herba selected among the medium-sugar-content single herbal medicines were subjected to massive extraction, and then the concentrates thereof were prepared.
- the concentrate of each extract was divided into concentrates for two-type purposes. That is, a concentrate for seed preparation and a concentrate for fluidized bed coating were separately prepared.
- Each kind of single herbal medicine was immersed in purified water for 30 min after the purified water was added at a weight of 250 kg per 25 kg of the single herbal medicine, and then subjected to extraction at 95-100°C for 3 h, and thereafter, the 10-fold water extract was transferred to a reduced pressure concentrator, and then concentrated under reduced pressure while the temperature was maintained at 60°C.
- the 10-fold water extract 1/3 of the extract and 2/3 of the extract were concentrated to have different sugar contents for seeds and for a fluidized bed, respectively.
- the concentration for fluidized bed coating and the concentrate for seed preparation having different sugar contents were separately prepared.
- the sugar content was measured by Atago digital saccharometer (Pal-3) and the content of solids was measured by an infrared moisture analyzer (FD-720, KETT Electronic, Japan), and calculated.
- Table 9 shows the results of extraction and concentration.
- concentration of the Atractylodis Rhizoma extract and the recovery of an essential oily layer will be described in detail in Example 3.4 below.
- Pinelliae Rhizoma, Cinnamomi Cortex Spissus, Aurantii Immaturus Fructus, Bupleuri Radix, and Magnoliae Cortex selected among the low-sugar-content single herbal medicines were subjected to massive extraction, and then the concentrates thereof were prepared.
- the concentrate of each extract was divided into concentrates for two-type purposes. That is, a concentrate for seed preparation and a concentrate for fluidized bed coating were separately prepared.
- Each kind of single herbal medicine was immersed in purified water for 30 min after the purified water was added at a weight of 1000 kg per 100 kg of the single herbal medicine, and then subjected to extraction at 95-100°C for 3 h, and thereafter, the 10-fold water extract was transferred to a reduced pressure concentrator, and then concentrated under reduced pressure while the temperature was maintained at 60°C.
- a 10-fold purified water was added to 150 kg of the herbal medicine.
- 1/3 of the extract and 2/3 of the extract were concentrated to have different sugar contents for seeds and for a fluidized bed, respectively.
- the concentration for fluidized bed coating and the concentrate for seed preparation having different sugar contents were separately prepared.
- the sugar content was measured by Atago digital saccharometer (Pal-3) and the content of solids was measured by an infrared moisture analyzer (FD-720, KETT Electronic, Japan), and calculated.
- Table 10 shows the results of extraction and concentration.
- concentration of the Cinnamomi Cortex Spissus extract and the recovery of an essential oily layer will be described in detail in Example 3.4 below.
- the content ranges of sugar and solids in extracts of complex herbal decoctions each composed of two or more single herbal medicines were almost similar to physical properties of the single herbal medicines, and thus one kind of complex herbal medicines representing each sugar content range was selected. Gumiganghwal-tang, Mahwang-tang, and Doinseunggi-tang were selected as representatives for respective sugar content standards, and extraction and concentrate preparation were carried out in the same manner as in single herbal medicines.
- Gumigangh wal-tang and Mahwang-tang as complex herbal decoctions were immersed in purified water for 30 min after the purified water was added at a weight of 500 kg per 50 kg of the complex herbal medicine, and Doinseunggi-tang as a complex herbal decoction was immersed in purified water for 30 min after the purified water was added at a weight of 1000 kg per 100 kg of the complex herbal medicine, and then subjected to extraction at 95-100°C for 3 h. Thereafter, each of the 10-fold water extracts was transferred to a reduced pressure concentrator, and then concentrated under reduced pressure while the temperature was maintained at 60°C.
- aroma component refers to an essential oil
- most of essential oil components contained in plant medicinal herbs include monoterpenes and sesquiterpenes. In some cases, these components are volatilized in a significant amount during extraction and concentrate preparation, and thus are hardly contained in the obtained extract concentrates.
- Atractylodis Rhizoma Cinnamomi Cortex Spissus, and Gumiganghwal-tang, which is a complex herbal medicine and contains Notopterygii Rhizoma, Saposhnikovia Radix, and Atractylodis Rhizoma
- the conditions for extraction and concentration were the same as in Examples 2, 3, and 4, but the selected samples were extracted and concentrated in a concentrator equipped with a device for recovering an essential oil layer.
- a raw material or a mixed herbal medicine (25 kg of Atractylodis Rhizoma, 100 kg of Cinnamomi Cortex Spissus, and 50 kg of Gumiganghwal-tang ) was immersed in a 10-fold weight of purified water for 30 min before extraction, and then subjected to extraction at 95-100°C for 3 h. Thereafter, the extract was transferred to a reduced pressure concentrator, and then concentrated under reduced pressure while the temperature was maintained at 55-60°C.
- a tube through which steam passes was provided at the top portion of the concentrator to which the 10-fold water extract was transferred, and the tube was connected to a condenser in which vaporized steam can be converted into a liquid state.
- the liquid passing through the condenser was allowed to primarily stand in a tank for condensate water, and then separated into an essential oil component layer and a water portion in an easily detachable liquid separator.
- a liquid separator marked with units capable of measuring volume was used.
- Table 12 shows the essential oil recovery results in the preparation process of the concentrates used for seeds and for a fluidized bed. The sugar contents of the respective use-specific concentrates were the same as the above results.
- [Table 12] Volumes of essential oil produced by concentration of Atractylodis Rhizoma, Cinnamomi Cortex Spissus, and Gumiganghwal-tang extracts Classific ation Herbal medicine + purified water, kg 10-fold water extract produced, kg Concentrate produced, kg Essential oil recovered, ml Total For seeds For fluid ized bed For seeds For fluid ized bed For seeds For fluid ized bed For seeds For fluid ized bed Atractylo dis rhizoma 25 + 250 188 60 128 5.6 17.5 165 310 Cinnamomi cortex spissus 100 + 1000 850 300 550 8.5 28.7 205 375 Gumigangh wal-tang 50 + 500 388 130 258 15.8 67.9 53 102
- the essential oil layers were used by calculating the weight percentages of the respective concentrates used for seed preparation and for a fluidized bed process, summing respective portions calculated according to the corresponding ratios to calculate the total amount of the essential oil, and encapsulating the total amount of the essential oil and adding the essential oil to a spray solution prepared for a fluidized bed.
- the essential oil layer was separated, and an oil component was encapsulated using alginic acid or beta-cyclodextrin (Table 13). Thereafter, as shown in FIG. 6 , the precipitated slurry layer was added to a preparation solution for a fluidized bed, and used together for coating.
- Cinnamomi Cortex Spissus essential oil 147 g was also encapsulated by the same method. After centrifugation and supernatant removal, 325 g of an inclusion product of Cinnamomi Cortex Spissus essential oil was recovered.
- Table 14 shows the characterization results of capsules in which an essential oil was encapsulated.
- a coating material for encapsulating an essential oil was sufficiently used with reference to known literature, and the essential oil used was evaluated as being 100% encapsulated since the smell emitted from the reaction product was hardly detected.
- the products separated after the reaction were taken equally at 5 g, and used in the measurement of the moisture content, and the remainders were added in the preparation of the extract concentrate for coating used in the fluidized bed process.
- the essential oil content of the dried capsules was evaluated 52.2% for Atractylodis Rhizoma, 56.6% for Cinnamomi Cortex Spissus, and 20.5% for Gumiganghwal-tang.
- An electronic nose was used to measure the intensity of aroma components.
- the measurement was carried out by an electronic nose sensor system using the PEN 3 Portable Electronic Nose (Airsense Analytics GmbH, Germany) equipped with 10 different metal oxides semi-conducting (MOS) sensors with high sensitivity and rapid response in the measurement of volatile organic compounds.
- the measurement was repeated three times, and the measurement results were expressed as the average measurement value (sensor response signal) by DC mV, and the intensity as a measurement value was compared under the same conditions.
- the measured samples were 10-fold water extracts, two types of concentrates (extract concentrates for seed preparation and for fluidized bed coating), and two types of spherical pellets (addition with and without essential oil-encapsulating capsule liquid).
- Five types of samples were taken at a weight corresponding to 1 g on the basis of the content of extracted solids, and 10 g of spherical pellets as dried samples were powdered in a mortar, and 1 g was taken based on the extract solids.
- Each sample except for the 10-fold water extract was corrected to the same weight by making up for a portion lacking in weight on the basis of the 10-fold water extract through the addition of distilled water.
- the weights of the 10-fold water extracts of Atractylodis Rhizoma (Table 9), Cinnamomi Cortex Spissus (Table 10), and Gumiganghwal-tang (Table 11), corresponding to 1 g of extract solids, were 20, 66.7, and 13.9 g, respectively.
- the Atractylodis Rhizoma and Gumiganghwal-tang samples were placed in 50 ml-glass vials and Cinnamomi Cortex Spissus was placed in 100 ml-glass vials, and then sealed with septum screw caps, followed by mixing. The vials were allowed to stand in a constant-temperature water bath at 60°C for 30 min.
- the gas flow rate was 30 ml/min
- the gas sampling time was 40 s
- the measurement time was 20 s
- the zero washing time was 180 s.
- the top portions of 50 ml-beakers containing distilled water were sealed with silver foil, and then allowed to stand in a constant-temperature water in the same conditions, followed by washing with washing gas.
- the percentage of the aroma component contained in final spherical pellets was 60-80% when the essential oil volatilized in the concentration process was recovered and returned, and the aroma level was 4-17% without the addition of the encapsulated essential oil slurry, indicating a significant difference.
- the preparation of seeds for single herbal medicines and complex herbal medicines was configured of: manufacturing square-cylindrical pellets by an extruder; and then grinding the pellets in a spheronizer to manufacture spherical pellets.
- a primary product by an extruder in order to solve problems in the manufacturing method discussed above, the kinds, mutual ratio, and levels of excipients added in an extract concentrate prepared for seed preparation, and the moisture content of a kneaded product mixed with the excipients were adjusted.
- Table 16 shows preparation conditions of seeds.
- the excipients used were classified into a mineral additive, a releasing agent, and an emulsifier.
- At least one of precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide, calcium silicate, magnesium silicate, silicon dioxide, titanium dioxide, bentonite, kaolin, and talc was selected and used as a mineral additive;
- at least one of microcrystalline cellulose (MCC), lactose, stearic acid-magnesium, stearic acid-calcium, PEG 6000, beta-cyclodextrin powder, zein powder, and starch sodium octenyl succinate (SSOC) was used as a releasing agent; and a sucrose fatty acid ester powder was used as an emulsifier.
- the high-sugar-content materials selected above were Jujubae Fructus, Fraxini Cortex, Ginseng Radix, Glycyrrhizae Radix, and Scutellariae Radix.
- the preparation of kneaded products added with excipients for seed preparation will be described in detail.
- a mineral additive As a mineral additive, at least one selected from precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide (MgO), calcium silicate (CaSiO 3 ), magnesium silicate (3MgSiO 3 ⁇ 5H 2 O), silicon dioxide (SiO 2 ), titanium dioxide (TiO 2 ), bentonite, kaolin, and talc was used. As for the standard of use, the mineral additive is contained in 25-15% per 100 g of the total excipients.
- At least one kind selected from microcrystalline cellulose (MCC), lactose, stearic acid-magnesium (stearate-Mg), stearic acid-calcium (stearate-Ca), PEG 6000, beta-cyclodextrin (CD) powder, zein powder, and starch sodium octenyl succinate (SSOC) was used as a releasing agent, and a sucrose fatty acid ester powder was used as an emulsifier.
- the release agent was contained in 74-83% per 100 g of the total excipients, and the emulsifier accounted for the remainder 1-2%. Table 17 details the use of excipients.
- the excipients required for treatment were first well mixed, and then mixed with an extract concentrate, and the prepared mix kneaded product was checked for the moisture content.
- the moisture content of the mix kneaded product of 2000 g of a Jujubae Fructus extract and 2050 g of excipients was analyzed to be 22.5%.
- Table 18 shows the detailed results of preparations for extrusion with respect to five kinds of high-sugar-content single herbal medicines.
- the product molded in a square-cylindrical shape was dried over air at room temperature overnight, and then subjected to a grinding step by a spheronizer for manufacturing spherical pellets.
- the square-cylindrical product molded by an extruder was dried over air at room temperature overnight, thereby obtaining 3847.5 g of Jujubae Fructus, 3439 g of Fraxini Cortex, 3344 g of Ginseng Radix, 3106.5 g of Glycyrrhizae Radix, and 2888 g of Scutellariae Radix.
- Each of the single herbal medicines was ground seven times while the weight for grinding once was 200 g.
- Spherical pellets with a size selected after sieving were measured for hardness by using a hardness tester (USA, Copley Scientific, Hardness Tester Model TBF1000), and the breaking force was measured by a load cell at a rate of 0.2 mm/sect and expressed as kgf.
- Table 19 shows the spheronization conditions and results, and the sieving results were expressed as an average value.
- Spheronization results of square-cylindrical pellets of high-sugar-content materials Spheronizer High-sugar-content materials Jujubae Fructus Fraxini Cortex Ginseng Radix Glycyrrhiz ae Radix Scutellari ae Radix Grinding rate, rpm, and time 1500rpm x 10min dose, g/once 200 Sieving, mm g % g % % g % g % 1.40 or more - - - - - - - - - 1.40-1.18 - - - - - - - 112.7 56.
- the spherical pellets used as seeds in a fluidized bed apparatus after grinding had a size of 1.18-0.85 mm for Jujubae Fructus, Fraxini Cortex, and Ginseng Radix and a size of 1.4-1.0 mm for Glycyrrhizae Radix and Scutellariae Radix.
- Jujubae Fructus 1302 g, Fraxini Cortex 1302 g, Ginseng Radix 1330 g, Glycyrrhizae Radix 1309 g, and Scutellariae Radix 1330g were made into the products suitable for use in a fluidized bed granulator, and the production efficiency compared with the input amount was shown to be in the range of 93-95%.
- the weight of spherical seeds introduced into the fluidized bed granulator was in the range of 1000-1300 g.
- the western medicines are finished products, and the above hardness level range corresponds to suitable levels to sufficiently prevent damage to the finished products due to shaking or friction during distribution, but in cases of the present application, the prepared seeds are semifinished products, and during a subsequent fluidized bed process, a higher level of hardness thereof is more suitable since consecutive impacts and friction are induced by the spray pressure of a preparation solution and particles move infinitely up and down.
- a fluidized bed granulator which is performed below, debris and the like due to friction and abrasion were not found, and the surfaces of the finished products were also clean.
- the hardness of the existing sugar spheres was in the range of 0.85-1.58 kgf, and sugar spheres having an average hardness of 1.25 kgf, when used as seeds for a fluidized bed, were highly likely to break or smash.
- the medium-sugar-content materials selected above were Atractylodis Rhizoma, Coptidis Rhizoma, Zingiberis Rhizoma Recens, Paeoniae Radix, and Ephedrae Herba. The preparation of kneaded products added with excipients for seed preparation will be described in detail.
- a mineral additive As a mineral additive, at least one selected from precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide (MgO), calcium silicate (CaSiO 3 ), magnesium silicate (3MgSiO 3 ⁇ 5H 2 O), silicon dioxide (SiO 2 ), titanium dioxide (TiO 2 ), bentonite, kaolin, and talc was used. As for the standard of use, the mineral additive is contained in 10-20% per 100 g of the total excipients.
- At least one kind selected from microcrystalline cellulose (MCC), lactose, stearic acid-magnesium (stearate-Mg), stearic acid-calcium (stearate-Ca), PEG 6000, beta-cyclodextrin (CD) powder, zein powder, and starch sodium octenyl succinate (SSOC) was used as a releasing agent, and a sucrose fatty acid ester powder was used as an emulsifier.
- the release agent was contained in 78-88% per 100 g of the total excipients, and the emulsifier accounted for the remainder 1-2%. Table 20 details the use of excipients.
- the excipients required for treatment were first well mixed, and then mixed with an extract concentrate, and the prepared mix kneaded product was checked for the moisture content.
- the moisture content of the mix kneaded product of 2500 g of an Atractylodis Rhizoma extract and 1640 g of excipients was analyzed to be 27.9%.
- Table 21 shows the detailed results of preparations for extrusion with respect to five kinds of medium-sugar-content single herbal medicines.
- the product molded in a square-cylindrical shape was dried over air at room temperature overnight, and then subjected to a grinding step by a spheronizer for manufacturing spherical pellets.
- the square-cylindrical product molded by an extruder was dried over air at room temperature overnight, thereby obtaining 3920 g of Atractylodis Rhizoma, 4435 g of Coptidis Rhizoma, 3550 g of Zingiberis Rhizoma Recens, 3465 g of Paeoniae Radix, and 3835 g of Ephedrae Herba.
- Each of the single herbal medicines was ground seven times while the weight for grinding once was 200 g.
- Spherical pellets used in the fluidized bed granulator after sieving were measured for hardness by using a hardness tester (USA, Copley Scientific, Hardness Tester Model TBF1000), and the breaking force was measured by a load cell at a rate of 0.2 mm/sect and expressed as kgf.
- Table 22 shows the spheronization conditions and results, and the sieving results were expressed as an average value.
- the amount of products with a size suitable for the standard was 1300 g for Atractylodis Rhizoma, 1325 g for Coptidis Rhizoma, 1275 g for Zingiberis Rhizoma Recens, 1300 g for Paeoniae Radix, and 1345 g for Ephedrae Herba, and the production efficiency of standardized products compared with the input amount was shown to be in the range of 91-96%.
- the measured hardness range of the spherical pellets having a selected size was measured to be a similar range to the seeds of the high-sugar-content herbal medicines.
- the low-sugar-content materials selected above were Pinelliae Rhizoma, Cinnamomi Cortex Spissus, Aurantii Immaturus Fructus, Bupleuri Radix, and Magnoliae Cortex.
- the preparation of kneaded products added with excipients for seed preparation will be described in detail.
- a mineral additive As a mineral additive, at least one selected from precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide (MgO), calcium silicate (CaSiO 3 ), magnesium silicate (3MgSiO 3 ⁇ 5H 2 O), silicon dioxide (SiO 2 ), titanium dioxide (TiO 2 ), bentonite, kaolin, and talc was used. As for the standard of use, the mineral additive is contained in 5-15% per 100 g of the total excipients.
- At least one kind selected from microcrystalline cellulose (MCC), lactose, stearic acid-magnesium (stearate-Mg) , stearic acid-calcium (stearate-Ca), PEG 6000, beta-cyclodextrin (CD) powder, zein powder, and starch sodium octenyl succinate (SSOC) was used as a releasing agent, and a sucrose fatty acid ester powder was used as an emulsifier.
- the release agent was contained in 83-94% per 100 g of the total excipients, and the emulsifier accounted for the remainder 1-2%. Table 23 details the use of excipients.
- the excipients required for treatment were first well mixed, and then mixed with an extract concentrate, and the prepared mix kneaded product was checked for the moisture content.
- the moisture content of the mix kneaded product of 4000 g of a Pinelliae Rhizoma extract and 2420 g of excipients was analyzed to be 24.6%.
- Table 24 shows the detailed results of preparations for extrusion with respect to five kinds of low-sugar-content single herbal medicines.
- the product molded in a square-cylindrical shape was dried over air at room temperature overnight, and then subjected to a grinding step by a spheronizer for manufacturing spherical pellets.
- the square-cylindrical product molded by an extruder was dried over air at room temperature overnight, thereby obtaining 6100 g of Pinelliae Rhizoma, 5560 g of Cinnamomi Cortex Spissus, 5285 g of Aurantii Immaturus Fructus, 6415 g of Bupleuri Radix, and 5055 g of Magnoliae Cortex.
- Each of the single herbal medicines was ground seven times while the weight for grinding once was 200 g.
- Spherical pellets used in the fluidized bed apparatus after sieving were measured for hardness by using a hardness tester (USA, Copley Scientific, Hardness Tester Model TBF1000), and the breaking force was measured by a load cell at a rate of 0.2 mm/sect and expressed as kgf.
- Table 25 shows the spheronization conditions and results, and the sieving results were expressed as an average value [Table 25] Spheronization results of square-cylindrical pellets of low-sugar-content materials Spheronizer Low-sugar-content materials Pinelliae Rhizoma Cinnamomi Cortex Spissus Aurantii Immaturus Fructus Bupleuri Radix Magnoliae Cortex Grinding rate, rpm, and time 1500rpm x 10min Dose, g 200 Sieving, mm g % g % % % % % 1.40 or more 1.40-1.18 105.8 52.9 95.3 47.7 102.3 51. 2 114.0 57. 0 107. 6 53.
- the spherical pellets of low-sugar-content herbal medicines, used as seeds in a fluidized bed granulator after grinding were all 1.40-1.00 mm in size.
- the amount of products with a size suitable for the standard was 1320 g of Pinelliae Rhizoma, 1255 g of Cinnamomi Cortex Spissus, 1295 g of Aurantii Immaturus Fructus, 1325 g of Bupleuri Radix, and 1320 g of Magnoliae Cortex, and the production efficiency of standardized products compared with the input amount was shown to be in the range of 89-95%, showing 94.3% for Pinelliae Rhizoma, 89.6% for Cinnamomi Cortex Spissus, 92.5% for Aurantii Immaturus Fructus, 94.6% for Bupleuri Radix, and 94.3% for Magnoliae Cortex.
- the measured hardness range of the spherical pellets having a selected size was measured to
- the preparation of seeds containing complex herbal decoction concentrates was also carried out under the same conditions for preparing seeds of single herbal medicines, as show in the general seed preparation conditions of Table 16.
- the complex herbal decoctions representing respective sugar content types were Gumiganghwal-tang, Mahwang-tang, Doinseunggi-tang.
- a mineral additive As a mineral additive, at least one selected from precipitated calcium carbonate (precipitated CaCO 3 ), magnesium oxide (MgO), calcium silicate (CaSiO 3 ), magnesium silicate (3MgSiO 3 -5H 2 O), silicon dioxide (SiO 2 ), titanium dioxide (TiO 2 ), bentonite, kaolin, and talc was used.
- the kind and use range of a mineral additive were the same as in the single herbal medicines, that is, the mineral additive was contained in 15-25% for the high-sugar-content complex herbal decoction, 10-20% for the medium-sugar-content complex herbal decoction, and 5-15% for the low-sugar-content complex herbal decoction, relative to 100 g of the total excipients.
- At least one kind selected from microcrystalline cellulose (MCC), lactose, stearic acid-magnesium (stearate-Mg), stearic acid-calcium (stearate-Ca), PEG 6000, beta-cyclodextrin (CD) powder, zein powder, and starch sodium octenyl succinate (SSOC) was used as a releasing agent, and a sucrose fatty acid ester powder was used as an emulsifier.
- MMC microcrystalline cellulose
- lactose lactose
- stearic acid-magnesium stearate-Mg
- stearic acid-calcium stearate-Ca
- PEG 6000 beta-cyclodextrin
- CD beta-cyclodextrin
- zein powder zein powder
- starch sodium octenyl succinate (SSOC) was used as a releasing agent
- SSOC starch sodium octenyl succinate
- the excipients required for treatment were first well mixed, and then mixed with an extract concentrate, and the prepared mix kneaded product was checked for the moisture content.
- the moisture content of the mix kneaded product of 3000 g of a Gumiganghwal-tang extract and 1450 g of excipients was analyzed to be 27.7%.
- Table 27 shows the detailed results of preparations for extrusion with respect to the other two kinds of complex herbal decoctions.
- the product molded in a square-cylindrical shape was dried over air at room temperature overnight, and then subjected to a grinding step by a spheronizer for manufacturing spherical pellets.
- the square-cylindrical product molded by an extruder was dried over air at room temperature overnight, thereby obtaining 4190 g of Gumiganghwal-tang, 5045 g of Mahwang-tang, and 4770 g of Doinseunggi-tang.
- Each of the single herbal medicines was ground seven times while the weight for grinding once was 200 g.
- Spherical pellets used in the fluidized bed apparatus after sieving were measured for hardness by using a hardness tester (USA, Copley Scientific, Hardness Tester Model TBF1000), and the breaking force was measured by a load cell at a rate of 0.2 mm/sect and expressed as kgf.
- Table 28 shows the spheronization conditions and results, and the sieving results were expressed as an average value.
- the spherical pellets used as seeds in a fluidized bed granulator after grinding had a size of 1.18-0.85 mm for Gumi ganghwal-tangand a size of 1.40-1.00 mm for Mahwang-tang and Doinseunggi-tang.
- the amount of products with a size suitable for the standard was 1340 g of Gumiganghwal-tang seeds, and 1330 g and 1335 g of Mahwang-tang and Doinseunggi-tang seeds, respectively.
- the production efficiency of standardized products compared with the input amount was shown to be a level of 95%, which were similar for the above seeds.
- the measured hardness range of the spherical pellets having a selected size was measured to show a somewhat lower tendency in Doinseunggi-tang, which is a low-sugar-content herbal extract.
- Example 5 Concentrate coating in fluidized bed granulator using seeds
- a fluidized bed process may smoothen the surface of a final product and shape the final product as a clean sphere, but requires a long time for basic processes and has many problems, for example, as in a case of a high sugar content, the time for preparing a spray solution added with additives and the spray time are long, and thus the previously coated components are concentrated on surfaces, causing sticking between particles.
- the formulating through extrusion and grinding is somewhat easy compared with a fluidized bed process, but results in a non-favorable shape and surface. Therefore, in the present application, as many extract solids as possible are contained in the process of extrusion and grinding, and as small amounts as possible or an adequate amount of extract solids is used in the fluid bed process.
- the content range of extract solids contained in the final formulation was set according to the characteristics of extracts, and a test was conducted for the set range, and then the set range was adjusted again.
- the coating of an extract concentrate in a fluidized bed granulator was carried out according to the following sequence. That is, considering the characteristics of the extract concentrate for a fluidized bed granulator, prepared in the above examples, optimal excipients were selected and the additional amounts thereof were determined, and separately prepared essential oil capsules were added together to prepare a preparation solution for spraying.
- a preparation solution when a preparation solution is sprayed, sugar components are concentrated through the volatilization of moisture, causing a sharp increase in stickiness, resulting in the agglomeration of pellet particles (aggregate formation).
- the preparation solution to be sprayed is required to have appropriate viscosity and sticking strength, retain uniform spreadability on the particle surface, and prevent agglomeration by mitigating the sticking strength of sugar components. Therefore, in the present disclosure, in order to increase the extract solid content, the extract concentration degree in the concentrates for seed preparation was increased to allow the extract solids contained in the prepared seeds to be maintained at a high content, whereas the solid content and the sugar content of the extract concentrates used for a fluidized bed granulator were differently adjusted to have lower levels according to the characteristics of medicinal herbs.
- the ranges of excipients added to the extract concentrates for coating used in the fluidized bed process were set to 10-15, 5-10, and 3-8%, respectively (Table 29), and the kinds and additional amounts of excipients used were controlled (Table 31) to achieve prompt drying, and the solutions were concentrated so as not to have excessive sticking strength due to sugar components.
- the content of extract solids in the fluidized bed process was increased to a range of 20-25% (Table 29) to promptly manufacture spherical pellets containing ultimately desired solid extracts.
- Table 29 summarizes the manufacturing conditions of final spherical pellets by a fluidized bed process.
- the sugar content of the concentration for a fluidized bed was set to 10-15.
- Manufacturing conditions of final spherical pellets by fluidized bed process Classification Single and complex herbal medicines High Medium Low Seed extract solid content, % 35-55 45-65 50-70 Concentrate for fluidized bed, sugar content (brix) 15-35 25-45 20-35 Level of excipients added, % 10-15 5-10 3-8 Extract solid increase in fluidized bed process, % 20-25 20-25 20-25 Final pellet extract solid content, % 55-80 60-90 70-95
- the operating conditions of the fluidized bed granulator were summarized in Table 30.
- the final coating step refers to a coating step of ethyl cellulose (EC) or shellac dissolved in ethanol.
- EC ethyl cellulose
- additives selected through preliminary tests were delimited as additives in the present disclosure.
- the selected additives were a mixture of precipitated calcium carbonate, stearic acid-magnesium, and PEG6000, a mixture of HPMC, pullulan, and glutinous starch, and starch sodium octenyl succinate, and sucrose fatty acid ester was used as an emulsifier.
- Table 3 shows the details of mixing.
- the excipients were added in 10-15% for the high sugar content, 5-10% for the medium sugar content, and 3-8% for the low sugar content, on the basis of extract solids of a concentrate for a fluidized bed.
- EC or shellac was used for the final external coating of finished spherical pellets.
- the coating agent was used in 2% relative to the sum of the weight of seeds introduced into the fluidized bed apparatus and the weight of the dried matter of the preparation solution sprayed.
- the seeds containing extracts of Jujubae Fructus, Fraxini Cortex, Ginseng Radix, Glycyrrhizae Radix, and Scutellariae Radix, as high-sugar-content single herbal medicines, prepared above, were introduced at 1000 g for each case into a fluidized bed apparatus.
- a homogenized preparation solution was prepared by adding an extract concentrate for a fluidized bed required and additives required according to the level of extract solids contained in the finally completed spherical pellets.
- the levels and percentages of excipients added in the preparation of a preparation solution for fluidized bed spraying were in the range of 10-15% for a high-sugar-content herbal medicine as shown in Tables 31 and 32.
- the excipients were used in 15% for Jujubae Fructus, 12% for Fraxini Cortex, and 10% for Ginseng Radix, Glycyrrhizae Radix, and Scutellariae Radix.
- FIG. 7 shows that the transparent hard capsules were filled with the completed shapes for each case.
- the final step for completing the spherical pellets was a step wherein the extract concentrate for fluidized bed spraying prepared above for use in the fluidized bed apparatus was coated on the surfaces of the seeds.
- Table 32 below shows the amounts of the extract concentrates for fluidized bed coating used.
- the fluidized bed coating process of the seeds containing Jujubae Fructus extract solids, which were prepared as seeds of a high-sugar-content single herbal medicine will be described in detail.
- the other single herbal medicines and complex herbal medicines were also analyzed by the methods corresponding to the above.
- the manufacturing results of spherical pellets and images thereof are sequentially shown below.
- the content of extract solids contained in the actual spherical pellets obtained after the completion of the fluidized bed process or the total percentage of essential oil contained in the extract solids were calculated on the basis of actual weights obtained after the completion of the fluidized bed process.
- the seeds containing extracts of Atractylodis Rhizoma, Coptidis Rhizoma, Zingiberis Rhizoma Recens, Paeoniae Radix, and Ephedrae Herba, as medium-sugar-content single herbal medicines, prepared above, were introduced at 1000-1300 g for each case into a fluidized bed granulator.
- a homogenized preparation solution was prepared by adding a extract concentrate for a fluidized bed required and additives required according to the level of extract solids contained in the finally completed spherical pellets.
- the levels and percentages of excipients added in the preparation of a preparation solution for fluidized bed spraying were in the range of 5-10% for a medium-sugar-content herbal medicine as shown in Tables 31 and 33.
- the excipients were used in 10% for Atractylodis Rhizoma, 6% for Coptidis Rhizoma, 8% for Zingiberis Rhizoma Recens, 7% for Paeoniae Radix, and 5% for Ephedrae Herba.
- the single herbal medicines used were analyzed wherein the content of atractylodin in Atractylodis Rhizoma was 0.15%, the content of berberine in Coptidis Rhizoma was 4.2%, the content of 6-gingerol in Zingiberis Rhizoma Recens was 0.4%, the content of albiflorin and paeoniflorin in Paeoniae Radix was 2.5%, and the content of ephedrine in Ephedrae Herba was 1.51%.
- the contents of marker components contained in the completed spherical pellets are shown in Table 33.
- Atractylodis Rhizoma was used by adding 242 g of the essential oil-encapsulated slurry prepared above to the preparation solution, and the other herbal medicines were measured for the moisture content.
- the essential oil used was set to be 100% encapsulated and the content of essential oil contained in the slurry added to the preparation solution for a fluidized bed was calculated and specifically indicated in the manufacturing details of Atractylodis Rhizoma pellets in Table 33.
- a homogenized preparation solution was prepared by adding a extract concentrate for a fluidized bed required and additives required according to the level of extract solids contained in the finally completed spherical pellets.
- the levels and percentages of excipients added in the preparation of a preparation solution for fluidized bed spraying were in the range of 3-8% for a low-sugar-content herbal medicine as shown in Tables 31 and 34.
- the excipients were used in 4% for Pinelliae Rhizoma, 5% for Cinnamomi Cortex Spissus, 6% for Aurantii Immaturus Fructus, 8% for Bupleuri Radix, and 3% for Magnoliae Cortex.
- the final coating agent shellac was used in a content of 2% equally for all the cases.
- the single herbal medicines used were analyzed wherein the content of adenine in Pinelliae Rhizoma was 0.0006%, the content of cinnamic acid in Cinnamomi Cortex Spissus was 0.04%, the content of poncirin and naringin in Aurantii Immaturus Fructus was 3.2%, the content of saikosaponin in Bupleuri Radix was 0.4%, and the content of magnolol and honokiol in Magnoliae Cortex was 1.5%.
- the contents of marker components contained in the completed spherical pellets are shown in Table 34.
- Cinnamomi Cortex Spissus was used by adding 320 g of the essential oil-encapsulated slurry prepared above to the preparation solution, and the other herbal medicines were measured for the moisture content.
- the essential oil used was set to be 100% encapsulated and the content of essential oil contained in the slurry added to the preparation solution for a fluidized bed was calculated and specifically indicated in the manufacturing details of Cinnamomi Cortex Spissus pellets in Table 34.
- the final spherical pellets of complex herbal decoctions were also manufactured under the same conditions as in the single herbal medicines.
- Doinseunggi-tang as a low-sugar-content complex herbal medicine were coated with respective extract solid concentrates in a fluidized bed apparatus to increase the content of extract solids.
- the seeds were introduced at 1000-1300 g for each case into the fluidized bed granulator.
- a homogenized preparation solution was prepared by adding the extract concentrate for a fluidized bed required and additives required according to the level of extract solids contained in the finally completed spherical pellets.
- the levels and percentages of excipients added in the manufacture of a preparation solution for fluidized bed spraying are as shown in Tables 29 and 31 and the actual use amounts are as shown in Table 35.
- the excipients are in the range of 10-15% for a high-sugar-content complex herbal medicine, and were used in 12% in Gumiganghwal-tang concentrate prepared for a fluidized bed; the excipients are in the range of 5-10% for a medium-sugar-content complex herbal medicine, and were used in 8% in the prepared Mahwang-tang concentrate; and the excipients are in the range of 3-8% for a low-sugar-content complex herbal medicine, and were used in 5% in the prepared Doinseunggi-tang concentrate.
- Gumiganghwal-tang was used by adding 125 g of the essential oil-encapsulated slurry prepared above to the preparation solution, and the other herbal medicines were measured for the moisture content.
- the essential oil used was set to be 100% encapsulated and the content of essential oil contained in the slurry added to the preparation solution for a fluidized bed was calculated and specifically indicated in the manufacturing details of pellets in Table 35.
- FIG. 10 shows that the transparent hard capsules were filled with the completed shapes for each case.
- the intake weight of the inventive single herbal medicines for a single dose was showed be less 26.82% in Pyeongwisan, 41.93% less in Banhasasim-tang, 44.28% less in Sosiho-tang, 43.25% less in Sihogyeji-tang, 32.76% less in Hubak-tang, and 36.23% less in Ijung-tang.
- the weights of single herbal medicines which are important in a single herbal mix medicine, were increased by 2 times.
- the weights of Atractylodis Rhizoma, Fraxini Cortex, and Magnoliae Cortex were increased for Pyeongwisan
- the weights of Pinelliae Rhizoma and Scutellariae Radix were increased for Banhasasim-tang
- the weights of Bupleuri Radix and Scutellariae Radix were increased for Sosiho-tang
- the weights of Bupleuri Radix, Pinelliae Rhizoma, and Ginseng Radix were increased for Sihogyeji-tang
- the weights of Magnoliae Corte and Aurantii Immaturus Fructus were increased for Hubak-tang.
- modified prescription refers to a different preparation for which "a corresponding marker component is enriched” or the content of at least one marker component recognized as having a weight of a supply source is increased.
- Furano diterpenoid contained in Scutellariae Radix which is a single herbal medicine included in Hwangnyeonhaedok-tang and Bangpungtongseongsan causes liver damage due to glutathione depletion; exposure to cinnamon bark and Cinnamomi Cortex Spissus in high concentrations for a long period causes liver toxicity; saikosaponin a, which is a marker component contained in Bupleuri Radix, inhibits lipid metabolism; a component of Glycyrrhizae Radix causes hypokalemia; aconitin of Pulvis Aconiti Tuberis Purificatum causes ventricular arrhythmia; and ephedrine, which is a marker component in Ephedrae Herba, causes arrhythmia and myocardial infarction ( J. Pharm. Soc. Korea 1998,42(4): 422-430 , J. Korean Med. 2017, 38(3): 170-184 , J. Korean Neurol. Asso
- the single herbal medicine of the present application has a great advantage in that the content of extract solids administered to humans is adjusted easily and accurately, and in the event of side effects, the accurate understanding of causes thereof and the derivation of remedies are easily attained.
- Example 7 Prescription of adding single herbal medicine to complex herbal medicine and use thereof
- Ephedrae Herba is the most frequently used medicinal herb by a prescription of a complex herbal medicine or a single herbal medicine relevant to obesity treatment in Korea.
- Ephedrine which is a marker component of Ephedrae Herba, works as a sympatheticomimetic agent acting on adrenoreceptors and exerts effects of suppressing appetite and promoting heat metabolism, leading to weight loss, and thus Ephedrae Herba is frequently used in prescriptions for diet.
- Ephedrae Herba needs special attention for side effects, such as insomnia, anxiety, headache, and palpitations, and cardiovascular side effects, such as myocardial infarction and arrhythmia.
- Mahwang-tang is a toxic herbal medicine containing an alkaloid component, wherein the content of the marker component ephedrine needs to be precisely controlled to be appropriate for the situation of a patient.
- ephedrine as an obesity medicine is reported in the range of 20-70 mg/day, but a lot of attention is required for more than 60 mg.
- a basic mahwhang-tang medicine containing a low content of ephedrine is manufactured as a complex herbal medicine and a single herbal medicine containing only Ephedrae Herba is manufactured (Table 33), so that four types of gamibang prescriptions having different ephedrine contents by stages of obesity treatment can be easily configured.
- FIG. 11 shows a chromatogram of the analysis of ephedrine of the complex herbal medicine mahwhang-tang (Table 35).
- the total ephedrine content of the dried Ephedrae Herba used was measured to be 15.05 mg/g, and the total content of ephedrine included in the two kinds of medicines was 28.116 mg/g for the single herbal medicine (Table 33) and 14.254 mg/g for the mahwhang complex herbal medicine.
- the total intake of the medicines can be minimized by stages.
- the complex herbal medicine was required at 3.508 g/day, and at 2.470 g/day when Ephedrae Herba as a single herbal medicine was added. Therefore, in terms of the Ephedrae Herba single herbal medicine, the amount of the medicine administered can be reduced by 42.02%, leading to the reduction in discomfort for a patient who should ingest the single herbal medicine in large amounts.
- Gumiganghwal -tang is one of the most important prescriptions in oriental clinical practice, accounting for 6.1% of the total number of prescription days and 7.0% of the total pharmaceutical cost among 56 kinds of herbal medicines in Oriental Medical Health Insurance.
- the constituent raw materials of Gumiganghwal-tang were Notopterygii Rhizoma 5.625 g, Saposhnikovia Radix 5.625 g, Ligustici Rhizoma 4.5 g, Thujae Resina 4.5 g, Atractylodis Rhizoma 4.5 g, Scutellariae Radix 4.5 g, Rehmanniae Radix 4.5 g, Asari Herba Cum Radix 1.875 g, Glycyrrhizae Radix 1.875 g, and the weight for a single dose of medicinal herbs was 37.5 g. The use will be described in detail with reference to the above example.
- a patient who comes to a hospital receiving single and complex herbal medicines can receive prescription drugs promptly on the spot according to the progress of disease symptoms. That is, as the important effects exerted by marker components of single herbal medicines constituting Gumiganghwal-tang, for example, it is known that Atractylodis Rhizoma exerts an effect on leg pain and joint pain, Scutellariae Radix exerts an edema relieving effect, and Glycyrrhizae Radix exerts on effect in the treatment of sore throat pain. Therefore, a doctor can provide the patient with a modified prescription by easily selecting which corresponding single herbal medicines manufactured above.
- a formulation system for individually customized herbal medicines by Korean Patent Registration No. 10-1681235 can be utilized. That is, a formulation system composed of software with an information program on information, efficacy, and the like of the above-described medicines and hardware configured to actually select, weighing, and packaging medicines is used.
- an oriental medical doctor can immediately select and mix a plurality of separate single herbal medicines on the basis of a prescription to be provided to a patient, and thus can immediately provide the same for the patient on the spot. Additionally, the oriental medical doctor can quickly respond to the increase or decrease of drug marker components, involved in the progress of symptoms after the patient visits a hospital.
- the manufactured single herbal medicine can be easily added to the prescription gamibang, in which the increase of important medicinal herbs is required even in complex herbal medicines that are usually administered. Ultimately, the contents of marker components actually provided to the patient can be accurately monitored.
- the present disclosure can easily established considering various factors including the age, weight, overall health conditions, gender, and regimen difference of a patient, personal drug metabolic rates, and severity of specific disorders or conditions. Furthermore, the present disclosure can provide a combination capable of administering one or more single herbal medicines or a prescription at the same time, or administering the single herbal medicines before or after the prescription or vice versa.
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Claims (17)
- Verfahren zum Herstellen einer Pelletformulierung, die einen einzelnen oder komplexen Kräuterextrakt enthält, wobei das Verfahren Folgendes umfasst:(a) Anfertigen eines Konzentrats für Samen und eines Konzentrats für Wirbelschicht-Coating aus einem einzelnen oder komplexen Kräuterextrakt, wobei das Konzentrat für Wirbelschicht-Coating einen niedrigeren Zuckergehalt als das Konzentrat für Samen aufweist;(b) Formen eines Samens durch Mischen des Konzentrats für Samen und eines Hilfsstoffs; und(c) Beschichten von Oberflächen der Samen durch Mischen des Konzentrats für Wirbelschicht-Coating und eines Hilfsstoffs,und wobei der Hilfsstoff mindestens eine Art ist, die aus der Gruppe ausgewählt ist, die aus Calciumcarbonat (ausgefälltes CaCO3), Magnesiumoxid (MgO), Calciumsilikat (CaSiO3), Magnesiumsilikat (3MgSiO3 5H2O), Siliziumdioxid (SiO2), Titandioxid (TiO2), Bentonit, Kaolin, Talk, CMC-Ca, Casein, Dextrin, Hydroxypropylmethylcellulose (HPMC), Pullulan, mikrokristalliner Cellulose (MCC), Lactose, Stearinsäure-Magnesium (Stearat-Mg), Stearinsäure-Calcium (Stearat-Ca), PEG 6000, Beta-Cyclodextrin-Pulver, Zeinpulver, Stärkenatriumoctenylsuccinat (SSOC) und Saccharose-Fettsäureestern besteht.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 5,5 oder mehr und weniger als 10,0 Brix aufweist, das Konzentrat für Samen in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 45-65 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 3,0 oder mehr und weniger als 5,5 Brix aufweist, das Konzentrat für Samen in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 40-60 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 0,01 oder mehr und weniger als 3,0 Brix aufweist, das Konzentrat für Samen in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 30-60 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 5,5 oder mehr und weniger als 10,0 Brix aufweist, das Konzentrat für Wirbelschicht-Coating in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 15-35 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 3,0 oder mehr und weniger als 5,5 Brix aufweist, das Konzentrat für Wirbelschicht-Coating in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 25-45 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 0,01 oder mehr und weniger als 3,0 Brix aufweist, das Konzentrat für Wirbelschicht-Coating in Schritt (a) durch Konzentrieren des einzelnen oder komplexen Kräuterextrakts auf einen Zuckergehalt von 20-35 Brix angefertigt wird.
- Verfahren nach Anspruch 1, wobei Schritt (b) Folgendes umfasst: Leiten eines Gemischs aus dem Konzentrat für Samen und dem Hilfsstoff durch einen Extruder, um ein Extrudat zu schneiden; und Einführen des geschnittenen Extrudats in einen Spheronizer, um das geschnittene Extrudat zu zerkleinern.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 5,5 oder mehr und weniger als 10,0 Brix aufweist, Schritt (b) durch Mischen eines Konzentrats für Samen, das 35-55 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts relativ zu dem Gesamttrockengewicht der Samen enthält, mit dem Rest eines Hilfsstoffs durchgeführt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 3,0 oder mehr und weniger als 5,5 Brix aufweist, Schritt (b) durch Mischen eines Konzentrats für Samen, das 45-65 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts relativ zu dem Gesamttrockengewicht der Samen enthält, mit dem Rest eines Hilfsstoffs durchgeführt wird.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 0,01 oder mehr und weniger als 3,0 Brix aufweist, Schritt (b) durch ein Konzentrat für Samen, das 50-70 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts relativ zu dem Gesamttrockengewicht der Samen enthält, mit dem Rest eines Hilfsstoffs durchgeführt wird.
- Verfahren nach Anspruch 1, wobei, wenn der einzelne oder komplexe Kräuterextrakt Aromatizität aufweist, das Verfahren ferner Folgendes umfasst: Erhalten eines ätherischen Öls, das während der Extraktion und Konzentrierung verflüchtigt wird; und Einkapseln des ätherischen Öls.
- Verfahren nach Anspruch 1, wobei, wenn der einzelne oder komplexe Kräuterextrakt Aromatizität aufweist, in Schritt (c) ein Produkt, das durch Einkapseln eines ätherischen Öls des Extrakts, der Aromatizität aufweist, erhalten wird, ferner zu dem Konzentrat für Wirbelschicht-Coating hinzugefügt und damit gemischt wird.
- Verfahren nach Anspruch 1, ferner zusätzlich umfassend Beschichten der Oberflächen der Samen nach Schritt (c).
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 5,5 oder mehr und weniger als 10,0 Brix aufweist, die Pelletformulierung relativ zu dem Gesamttrockengewicht davon 55-80 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts enthält.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 3,0 oder mehr und weniger als 5,5 Brix aufweist, die Pelletformulierung relativ zu dem Gesamttrockengewicht davon 60-90 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts enthält.
- Verfahren nach Anspruch 1, wobei, wenn ein 10-facher Wasserextrakt des einzelnen oder komplexen Kräuterarzneimittels in Schritt (a) einen Zuckergehalt von 0,01 oder mehr und weniger als 3,0 Brix aufweist, die Pelletformulierung relativ zu dem Gesamttrockengewicht davon 70-95 Gew.-% von Feststoffen des einzelnen oder komplexen Kräuterextrakts enthält.
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EP3782609A1 EP3782609A1 (de) | 2021-02-24 |
EP3782609B1 true EP3782609B1 (de) | 2023-11-01 |
EP3782609C0 EP3782609C0 (de) | 2023-11-01 |
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US (1) | US20210052504A1 (de) |
EP (1) | EP3782609B1 (de) |
JP (1) | JP6934983B2 (de) |
KR (1) | KR102088136B1 (de) |
CN (1) | CN112402390B (de) |
TW (1) | TWI808337B (de) |
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US20220032270A1 (en) * | 2017-10-13 | 2022-02-03 | W.M. Barr & Company, Inc. | Encapsulated fragrance in compressed tablet |
CN112697949B (zh) * | 2020-12-09 | 2022-05-27 | 浙江金城阜通制药有限公司 | 一种保元汤及其类似方提取物及制剂的薄层鉴别方法 |
CN113616600B (zh) * | 2021-08-05 | 2023-07-14 | 广东汇群中药饮片股份有限公司 | 一种治疗脾肺气虚症的中药复方颗粒及其制备方法 |
CN114617856B (zh) * | 2021-09-07 | 2023-04-07 | 辽宁格林希尔医疗科技有限公司 | 一种固液混悬中药制剂及其制备方法 |
CN115317588B (zh) * | 2022-09-26 | 2024-04-05 | 东阿阿胶股份有限公司 | 保元汤、保元浸膏、保元固体制剂的制备方法 |
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WO2008035354A1 (en) * | 2006-09-21 | 2008-03-27 | Unijules Life Sciences Ltd. | Pellets of herbal extracts and process for preparing the same |
CN107744510A (zh) * | 2017-10-25 | 2018-03-02 | 广东罗浮山国药股份有限公司 | 一种微丸型配方颗粒的制备方法 |
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JP4803969B2 (ja) * | 2004-03-31 | 2011-10-26 | 小林製薬株式会社 | 植物抽出物を含有する粒剤の製造方法 |
KR20040075804A (ko) | 2004-07-26 | 2004-08-30 | 최광철 | 도로용 현수막거치대 |
EP2026664B1 (de) * | 2006-05-19 | 2014-09-10 | Firmenich S.A. | Einstufiges sprühtrocknungsverfahren |
KR100896326B1 (ko) * | 2006-06-09 | 2009-05-07 | (주)일품인삼 | 고농도의 인삼 성분을 함유하는 인삼 엑기스 그래뉼 및환제의 제조방법 |
TWI436758B (zh) * | 2009-08-05 | 2014-05-11 | Ministry Of Health And Welfare | 一種濃縮中藥圓粒及其製造方法 |
JP2011197213A (ja) | 2010-03-18 | 2011-10-06 | Seiko Epson Corp | 液晶装置及び投射型表示装置 |
KR101481772B1 (ko) * | 2012-06-19 | 2015-01-14 | 주식회사 아리바이오 | 추출물을 고농도로 함유하는 과립 또는 환의 제조방법 |
KR101419462B1 (ko) * | 2012-07-11 | 2014-07-14 | 광동제약 주식회사 | 인습성이 개선된 생약 추출엑스를 포함하는 펠렛 제제 및 이의 제조방법 |
KR101681235B1 (ko) | 2014-12-31 | 2016-12-01 | (주)한의바이오 | 개인별 맞춤 한약 조제 시스템 |
JP6976675B2 (ja) * | 2015-03-31 | 2021-12-08 | 小林製薬株式会社 | 粉末または顆粒状の可食性植物乾燥組成物 |
KR101794860B1 (ko) * | 2016-01-29 | 2017-11-09 | 주식회사 홍삼단 | 홍삼농축액분말과 유동층코팅기를 이용한 홍삼농축액 알갱이의 제조방법 |
JP3214647U (ja) * | 2017-10-26 | 2018-02-01 | 森下仁丹株式会社 | 多層状球状粒子 |
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- 2020-06-03 JP JP2020096543A patent/JP6934983B2/ja active Active
- 2020-07-17 CN CN202010692403.2A patent/CN112402390B/zh active Active
- 2020-08-05 TW TW109126415A patent/TWI808337B/zh active
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CN107744510A (zh) * | 2017-10-25 | 2018-03-02 | 广东罗浮山国药股份有限公司 | 一种微丸型配方颗粒的制备方法 |
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TWI808337B (zh) | 2023-07-11 |
TW202108131A (zh) | 2021-03-01 |
EP3782609A1 (de) | 2021-02-24 |
CN112402390B (zh) | 2023-03-28 |
JP2021031488A (ja) | 2021-03-01 |
CN112402390A (zh) | 2021-02-26 |
KR102088136B1 (ko) | 2020-03-11 |
EP3782609C0 (de) | 2023-11-01 |
JP6934983B2 (ja) | 2021-09-15 |
US20210052504A1 (en) | 2021-02-25 |
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